Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/545—Heterocyclic compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• IRAK4 interleukin-1 receptor-associated kinase 4
• Protein degradation is a highly regulated and essential process that maintains cellular homeostasis.
• the selective identification and removal of damaged, misfolded, or excess proteins is achieved via the ubiquitin-proteasome pathway (UPP).
• UPP ubiquitin-proteasome pathway
• the UPP is central to the regulation of almost all cellular processes, including antigen processing, apoptosis, biogenesis of organelles, cell cycling, DNA transcription and repair, differentiation and development, immune response and inflammation, neural and muscular degeneration, morphogenesis of neural networks, modulation of cell surface receptors, ion channels and the secretory pathway, the response to stress and extracellular modulators, ribosome biogenesis and viral infection.
• E3 ubiquitin ligase Covalent attachment of multiple ubiquitin molecules by an E3 ubiquitin ligase to a terminal lysine residue marks the protein for proteasome degradation, where the protein is digested into small peptides and eventually into its constituent amino acids that serve as building blocks for new proteins.
• E3 ubiquitin ligases which facilitate the ubiquitination of different proteins in vivo, which can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s and multi-subunit E3s.
• the ubiquitin-proteasome pathway can be harnessed for therapeutic intervention by using chimeric compounds capable of activating the ubiquitination of a Target Protein, where the chimeric compound comprises a Target Protein binding element that is covalently linked to ubiquitination recognition element.
• Such chimeric compounds that are capable of binding a Target Protein and a ubiquitin ligase may cause the Target Protein to be selectively degraded via the UPP.
• the discovery for example, that thalidomide binds to the cereblon E3 ubiquitin ligase has led to research investigating the incorporation of thalidomide and certain derivatives into chimeric compounds for the targeted destruction of proteins.
• Protein kinases are a large multigene family consisting of more than 500 proteins which play a critical role in the development and treatment of a number of human diseases in oncology, neurology and immunology.
• Kinases catalyze the phosphorylation of proteins, lipids, sugars, nucleosides and other cellular metabolites and play key roles in all aspects of eukaryotic cell physiology.
• protein kinases and lipid kinases participate in the signaling events which control the activation, growth, differentiation and survival of cells in response to extracellular mediators or stimuli such as growth factors, cytokines or chemokines.
• protein kinases are classified in two groups, those that preferentially phosphorylate tyrosine residues and those that preferentially phosphorylate serine and/or threonine residues.
• Kinases are important therapeutic targets for the development of anti-inflammatory drugs (Cohen, 2009. Current Opinion in Cell Biology 21, 1-8), for example kinases that are involved in the orchestration of adaptive and innate immune responses. Many diseases are associated with abnormal cellular responses triggered by kinase-mediated events. Kinase targets of particular interest are members of the IRAK family.
• IRAKs interleukin-1 receptor-associated kinases
• TLRs toll-like receptors
• IRAK1 was first identified through biochemical purification of the IL-1 dependent kinase activity that co-immunoprecipitates with the IL-1 type 1 receptor (Cao et al., 1996. Science 271(5252): 1128-31).
• IRAK2 was identified by the search of the human expressed sequence tag (EST) database for sequences homologous to IRAK1 (Muzio et al., 1997. Science 278(5343): 1612-5).
• IRAK3 also called IRAKM was identified using a murine EST sequence encoding a polypeptide with significant homology to IRAK1 to screen a human phytohemagglutinin-activated peripheral blood leukocyte (PBL) cDNA library (Wesche et al., 1999. J. Biol. Chem. 274(27): 19403-10).
• IRAK4 was identified by database searching for IRAK-like sequences and PCR of a universal cDNA library (Li et al., 2002. Proc. Natl. Acad. Sci. USA 99(8):5567-5572).
• IRAK4 is thought to be the initial protein kinase activated downstream of the interleukin-1 (IL-1) receptor and all toll-like-receptors (TLRs) except TLR3, and initiates signaling in the innate immune system via the rapid activation of IRAK1 and slower activation of IRAK2.
• IL-1 interleukin-1
• TLRs toll-like-receptors
• IRAK4 plays an important role in signaling networks controlling inflammation, there is a great need to develop chimeric compounds capable of activating the ubiquitination and degradation of IRAK4 proteins. It is an object of the present disclosure to provide new compounds, methods, compositions and methods of manufacture that are useful for the selective degradation of IRAK4 protein in vivo via the ubiquitin-proteasome pathway (UPP).
• UFP ubiquitin-proteasome pathway
• the present disclosure is a compound of formula (A):
• the present disclosure provides methods of treating a disorder responsive to modulation of IRAK4 activity and/or degradation of IRAK4 in a subject comprising administering to the subject an effective amount of at least one compound described herein.
• the present disclosure also includes the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disorder responsive to modulation of IRAK4 activity and/or degradation of IRAK4.
• compounds described herein, or pharmaceutically acceptable salts thereof for use in treating a disorder responsive to modulation of IRAK4 activity and/or degradation of IRAK4.
• Compounds or pharmaceutically acceptable salts thereof as described herein are capable of activating the selective ubiqitination of IRAK4 proteins via the ubiquitin-proteasome pathways (UPP) and cause degradation of IRAK4 proteins.
• compounds or pharmaceutically acceptable salts thereof as described herein can modulate IRAK4 activities.
• IRAK4 function such as, for example, autoimmune disease, an inflammatory disease, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, Alzheimer's disease, Ischemic stroke, Cerebral Ischemia, hypoxia, TBI (Traumatic Brain Injury), CTE (Chronic Traumatic Encephalopathy), epilepsy, Parkinson's disease (PD), Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS).
• alkyl refers to a fully saturated branched or unbranched hydrocarbon moiety. In some embodiments, the alkyl comprises 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In some embodiments, an alkyl comprises from 6 to 20 carbon atoms.
• alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl.
• alkyl portion i.e., alkyl moiety
• alkoxy or a haloalkyl have the same definition as above.
• alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally, one to three substituents except in the case of halogen substituents such as perchloro or perfluoroalkyls).
• alkoxy refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (i.e., a —O—C 1-4 alkyl group wherein C 1-4 alkyl is as defined herein).
• Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy and the like.
• alkoxy groups have about 1-4 carbons, more preferably about 1-2 carbons.
• aryl refers to a carbocyclic (all carbon) aromatic monocyclic or bicyclic ring system containing 6-10 carbon atoms.
• 6-10 membered aryl groups include phenyl and naphthyl. In some embodiments, the aryl is phenyl.
• bridged ring system is a ring system where two non-adjacent atoms of the ring are connected (bridged) by one or more (preferably from one to three) atoms selected from C, N, O, and S. In one embodiment, a bridged ring system have from 6 to 8 ring members.
• fused ring system is a ring system that has two ring structures sharing two adjacent ring atoms. In one embodiment, a fused ring system have from 8 to 12 ring members.
• spiro ring system is a ring system that has two ring structures having one ring atom in common. In one embodiment, spiro ring systems have from 5 to 8 ring members.
• cycloalkyl refers to partially or fully saturated monocyclic or bicyclic or spiro hydrocarbon groups of 3-7 carbon atoms, 3-6 carbon atoms, or 5-7 carbon atoms.
• cycloalkyl is a 3- to 6-membered fully saturated monocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).
• carrier and “carbocyclic ring” refer to saturated or partially unsaturated (i.e., non-aromatic) monocyclic or bicyclic hydrocarbon groups of, for example, 3-10, 3-8, 3-7, 3-5, 3-6, 4-6, 5-7 or 7-10 carbon atoms.
• 3 to 7 membered monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopenentyl, cyclohexenyl, cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl and cycloheptatrienyl.
• Bicyclic carbocycles include, but are not limited to, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo-[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, spiro[2.2]pentanyl and spiro[3.3]heptanyl.
• 7 to 10 membered bicyclic carbocycles include, but are not limited to, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, bicyclo[3.3.0]octanyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[3.3.2]decanyl and decalinyl.
• bridged-carbocyclic ring refers to a cyclic moiety connected at two non-adjacent ring atoms of the carbocycle (e.g. bicyclo[1.1.1]pentane, bicyclo[2.2.1] heptane and bicyclo[3.2.1] octane).
• fused bicyclic ring system or “fused carbobicyclic ring system” refers to a carbocycle connected at two non-adjacent ring atoms of the carbocycle.
• Fused bicyclic ring systems include, but are not limited to, 1,2,3,4-tetrahydronaphthalene, (1S,5R)-1-methylbicyclo[3.1.0]hexane, bicyclo[3.1.0]hexane, bicyclo[4.1.0]heptane and 2,3-dihydro-1H-indene.
• spiro carbocyclic ring means a two-ring system wherein both rings share one common carbon atom.
• examples of spiro carbocyclic rings include spiro[2.5]octane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[3.4]octane and the like.
• Halogen or “halo” may be fluorine, chlorine, bromine or iodine (preferred halogens as substituents are fluorine and chlorine).
• haloalkyl or “halo-substituted alkyl” or refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms is replaced by a halo atom.
• the haloalkyl group can be monohalo-alkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl.
• a monohaloalkyl can have one iodo, bromo, chloro or fluoro within the alkyl group.
• Dihaloalkyl and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl.
• the polyhaloalkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups.
• haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
• a perhaloalkyl group refers to an alkyl group having all hydrogen atoms replaced with halo atoms.
• haloalkoxy refers to a fully saturated branched or unbranched haloalkyl moiety attached through an oxygen bridge (i.e., a —O—C 1-4 haloalkyl group wherein C 1-4 haloalkyl is as defined herein).
• heteroaryl refers to an aromatic 5- to 6-membered monocyclic or an 8- to 10-membered bicyclic ring system, having 1 to 4 heteroatoms independently selected from O, N and S, and wherein N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone.
• Examples of “5 or 6 membered heteroaryl” or “5- to 6-membered monocyclic heteroaryl” include, but are not limited to, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, and the like.
• a 5 to 6 membered heteroaryl is selected from pyrrolyl, pyridyl, pyrazolyl, thienyl, furanyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, imidazolyl, tetrazolyl, triazinyl, pyrimidyl, pyrazinyl, and thiazolyl.
• a 5 to 6 membered heteroaryl is selected from pyridinyl, pyrimidinyl, 2H-1,2,3-triazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyrazolyl and thienyl.
• Examples of a 5-membered heteroaryl include, but are not limited to, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadizolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl.
• Examples of 8- to 10-membered bicyclic heteroaryls include, but are not limited to, imidazolthiazolyl, imidazopyridinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, indazolyl, 2H-indazolyl, indolyl, isoindolyl, 2 ⁇ 2 -isoindolinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, purinyl, thienopyridinyl and thieno[3,2-b]pyridinyl.
• 9- to 10-membered bicyclic heteroaryls include, but are not imitated to, imidazopyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, 2H-indazolyl, indolyl, isoindolyl, 2 ⁇ 2 -isoindolinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, purinyl, thienopyridinyl and thieno[3,2-b]pyridinyl.
• a 5-membered heteroaryl is selected from
• a 6-membered heteroaryl is selected from
• Examples of 9 to 10 membered heteroaryls include indolyl, indazolyl, benzofuranyl, quinoxalinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isothiazolo[4,3-b]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, imidazo[1,2-b]pyridazinyl, thieno[2,3-b]pyrazinyl, 1H-benzo[d]imidazolyl, benzo[d]thiazolyl, 1,6-naphthyridinyl, and 1,5-naphthyridinyl.
• a 9 to 10 membered heteroaryl is selected from pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isothiazolo[4,3-b]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, imidazo[1,2-b]pyridazinyl, thieno[2,3-b]pyrazinyl, 1H-benzo[d]imidazolyl, benzo[d]thiazolyl, 1,6-naphthyridinyl, 1,5-naphthyridinyl, and 2H-indazolyl.
• a heteroaryl is an 8- to 9-membered bicyclic heteroaryl selected from:
• heterocycle refers to a monocyclic ring which is partially or fully saturated and contains 1 to 2 heteroatoms, independently selected from sulfur, oxygen and/or nitrogen.
• Monocyclic heterocycles include, but are not limited to, oxtanyl, tetrahydrofuranyl, dihydrofuranyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, piperidinyl, 1,3-dioxolanyl, pyrrolinyl, pyrrolidinyl, tetrahydropyranyl, oxathiolanyl, dithiolanyl, 1,3-dioxanyl, 1,3-dithianyl, oxathianyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, tetrahydro-thiopyran 1,1-dioxide, 1,4-diazepan
• a monocyclic heterocycle is selected from:
• bicyclic heterocycle refers to a bicyclic ring which is partially or fully saturated and contains 1 to 2 heteroatoms, independently selected from sulfur, oxygen and/or nitrogen.
• Bicyclic heterocycles include, but are not limited to, 2,6-diazaspiro[3.3]heptane and pyrazolo[1,5-a]pyrimidine.
• spiro bicyclic heterocycle refers to a fully saturated bicyclic heterocycle ring system having two ring structures with one ring atom in common.
• a spiro bicyclic heterocycle has from 7 to 11 ring members.
• partially or fully saturated heterocycle refers to a nonaromatic ring that is either partially or fully saturated and may exist as a single ring, bicyclic ring (including fused heterocyclic rings) or a spiro ring.
• the heterocyclic ring is generally a 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1, 2 or 3 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen.
• Partially saturated or fully saturated heterocyclic rings include groups such as epoxy, aziridinyl, azetidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, 1H-dihydroimidazolyl, hexahydropyrimidinyl, piperidinyl, piperazinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl, oxazinyl, morpholino, thiomorpholino, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, oxazolidinyl, thiazolidinyl, 7-oxabicyclo[2.2.1]heptane, and the like.
• Partially saturated heterocycles include, but are not limited to, pyridin-2(1H)-one.
• a partially saturated heterocyclic ring also includes groups wherein a heterocyclic ring is fused to an aryl or heteroaryl ring (e.g., 2,3-dihydrobenzo furanyl, indolinyl (or 2,3-dihydroindolyl), 2,3-dihydrobenzothiophenyl, 2,3-dihydro benzothiazolyl, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 1,2,3,4-tetrahydro quinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydropyrido[3,4-b]pyrazinyl).
• aryl or heteroaryl ring e.g., 2,3-dihydrobenzo furanyl, indolinyl (or 2,3
• a partially or fully saturated heterocycle is selected from:
• bridged-heterocyclic ring system refers to a 5 to 10 membered heterobicyclic moiety connected at two non-adjacent ring atoms of the heterocycle containing at least one heteroatom (e.g., oxygen, sulfur, nitrogen or combinations thereof) within a 5 to 10 membered cyclic ring system.
• heteroatom e.g., oxygen, sulfur, nitrogen or combinations thereof
• bridged-heterocyclic ring system examples include, but are not limited to, 2-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[4.1.0]heptane, 2-oxabicyclo[2.2.1]heptane, 2-oxabicyclo[2.2.2]octane, 8-oxabicyclo[3.2.1]octane, and 2,6-dioxabicyclo[3.2.1]octane.
• fused heterobicyclic ring system refers to two ring systems that share two adjacent ring atoms and at least one of the rings containing a ring atom that is a heteroatom selected from O, N and S.
• fused heterobicylic ring systems include, but are not limited to, 1,3-dihydroisobenzofuran, 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, pyrazolo[1,5-a]pyrimidine, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole, 6,7-dihydro-5H-cyclopenta[b]pyridine, 2-oxabicyclo[2.1.0]pentane, indolin-2-one, 2,3-dihydrobenzofuran, 1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline, 3,4-dihydroquinolin-2(1H)-one,
• a partially saturated heterocyclic ring also includes groups wherein the heterocyclic ring is fused to an aryl or heteroaryl ring (e.g., 2,3-dihydrobenzofuranyl, indolinyl (or 2,3-dihydro indolyl), 2,3-dihydrobenzothiophenyl, 2,3-dihydrobenzothiazolyl, 1,2,3,4-tetrahydro quinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydropyrido[3,4-b]pyrazinyl, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, and the like.
• “fused heterobicyclic ring system” refers fused bicyclic heteroaryl.
• the term “7 to 10 membered fused heterobicyclic ring system” is limited to a 7 to 10 membered bicyclic heteroaryl, such as pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-a]pyridine, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, isothiazolo[4,3-b]pyridine, pyrrolo[1,2-a]pyrimidine, pyrido[3,2-d]pyrimidine, imidazo[1,2-b]pyridazine, thieno[2,3-b]pyrazine, 1H-benzo[d]imidazole, benzo[d]thiazole, 1,6-naphthyridine and 1,5-naphthyridine.
• pyrazolo[1,5-a]pyrimidine such as pyrazolo[1,5-a]pyrimidine
• spiro heterobicyclic ring system means a two-ring system wherein both rings share one common atom.
• examples of spiro heterobicyclic ring systems include oxaspiro[2.4]heptanyl, 5-oxaspiro[2.4]heptanyl, 4-oxaspiro[2.4]heptane, 4-oxaspiro[2.5]octanyl, 6-oxaspiro[2.5]octanyl, oxaspiro[2.5]octanyl, oxaspiro[3.4]octanyl, oxaspiro[bicyclo[2.1.1]hexane-2,3′-oxetan]-1-yl, oxaspiro[bicyclo[3.2.0]heptane-6,1′-cyclobutan]-7-yl, 2,6-diazaspiro[3.3]heptanyl, -oxa-6-azas
• Hydroxyl or “Hydroxy” refers to the group —OH.
• oxo refers to an oxygen atom connected to a carbon or sulfur atom by a double bond.
• examples include carbonyl, sulfinyl, or sulfonyl groups (—C(O)—, —S(O)— or —S(O) 2 —) such as, a ketone, aldehyde, or part of an acid, ester, amide, lactone, or lactam group and the like.
• a group/variable e.g., L, Z 1 , Z 2 etc.
• bond when a group/variable (e.g., L, Z 1 , Z 2 etc.) is defined as “bond”, it means that the two moieties attached to the group/variable are connected directly to each other.
• L in Formula (A) when L in Formula (A) is a bond, it means that the IRAK moiety and the DSM moiety are connected directly.
• an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position.
• the term “compounds of the present disclosure” refers to compounds of formula (A), as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, isotopically labeled compounds (including deuterium substitutions), and inherently formed moieties (e.g., polymorphs, solvates and/or hydrates).
• salts are included as well, in particular pharmaceutically acceptable salts.
• salts refers to an acid addition or base addition salt of a compound of the disclosure. “Salts” include in particular “pharmaceutical acceptable salts”.
• pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of this disclosure and, which typically are not biologically or otherwise undesirable.
• the compounds of the present disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
• Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen
• Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
• Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
• Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
• Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
• the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
• Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
• Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
• the salts can be synthesized by conventional chemical methods from a compound containing a basic or acidic moiety. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
• the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like
• non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
• Lists of additional suitable salts can be found, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
• the disclosure provides deuterated compounds in which any or more positions occupied by hydrogen can include enrichment by deuterium above the natural abundance of deuterium.
• one or more hydrogen atoms are replaced with deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
• hydrogen is present at all positions at its natural abundance.
• Isotopically-labeled compounds of formula (A) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
• solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 -DMSO.
• an optical isomer or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present disclosure. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the disclosure includes enantiomers, diastereomers or racemates of the compound.
• Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term is used to designate a racemic mixture where appropriate.
• a single stereoisomer with known relative and absolute configuration of the two chiral centers is designated using the conventional RS system (e.g., (1S,2S)); a single stereoisomer with known relative configuration but unknown absolute configuration is designated with stars (e.g., (1R*,2R*)); and a racemate with two letters (e.g, (1RS,2RS) as a racemic mixture of (1R,2R) and (1S,2S); (1RS,2SR) as a racemic mixture of (1R,2S) and (1S,2R)).
• the conventional RS system e.g., (1S,2S
• stars e.g., (1R*,2R*
• a racemate with two letters e.g, (1RS,2RS
• (1RS,2SR as a racemic mixture of (1R,2S) and (1S,2R
• “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
• the absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system.
• the stereochemistry at each chiral carbon may be specified by either R or S.
• Resolved compounds whose absolute configuration is unknown can be designated (+) or ( ⁇ ) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
• the resolved compounds can be defined by the respective retention times for the corresponding enantiomers/diastereomers via chiral HPLC.
• Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)— or (S)—.
• Optically active (R)- and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., separated on chiral SFC or HPLC chromatography columns, such as CHIRALPAK® and CHIRALCEL® available from DAICEL Corp. using the appropriate solvent or mixture of solvents to achieve good separation). If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
• the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
• a “patient,” “subject” or “individual” are used interchangeably and refer to either a human or non-human animal.
• the term includes mammals such as humans.
• the animal is a mammal.
• a subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
• the subject is a primate.
• the subject is a human.
• phrases “pharmaceutically acceptable” indicates that the substance, composition or dosage form must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
• the term “treat”, “treating” or “treatment” of any disease or disorder refers to the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a compound of the present disclosure to prevent the onset of the symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition or disorder.
• stroke has the meaning normally accepted in the art.
• the term can broadly refer to the development of neurological deficits associated with the impaired blood flow regardless of cause. Potential causes include, but are not limited to, thrombosis, hemorrhage and embolism.
• ischemic stroke refers more specifically to a type of stroke that is of limited extent and caused due to a blockage of blood flow.
• a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment (preferably, a human).
• co-administer refers to the presence of two active agents in the blood of an individual. Active agents that are co-administered can be concurrently or sequentially delivered.
• composition therapy or “in combination with” or “pharmaceutical combination” refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure.
• administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients.
• administration encompasses co-administration in multiple, or in separate containers (e.g., capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to a desired dose prior to administration.
• such administration also encompasses use of each type of therapeutic agent being administered prior to, concurrent with, or sequentially to each other with no specific time limits.
• the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
• the compounds of the present disclosure comprise a degradation signaling moiety (DSM) that can bind to an E3 ligase (e.g., the cereblon protein), an IRAK4 binding or targeting moiety and optionally a Linker that covalently links the DSM to the IRAK4 binding or targeting moiety.
• DSM degradation signaling moiety
• the compound of the present disclosure is a compound of Formula (A):
• IRAK, L and DSM portions in Formula (A) as described in the first aspect above.
• the DSM, IRAK and Linker portions in Formula (A) are as described below.
• IRAK is an IRAK4 binding moiety represented by Formula (IA) or (IB):
• IRAK is an IRAK4 binding moiety represented by Formula (I), (IA) or (IB), wherein R 1 is selected from phenyl optionally substituted with 1 to 3 R 5 ; 5 or 6 membered heteroaryl having 1 to 2 nitrogen atoms, said heteroaryl is optionally substituted with 1 to 3 R 5 ; and 9 to 10 membered bicyclic heteroaryl having 1, 2 or 3 nitrogen atoms, said ring system is optionally substituted with 1 to 3 R 5 ; and the definitions for the other variables are as defined in the first embodiment.
• IRAK is an IRAK4 binding moiety represented by Formula (I), (IA) or (IB), wherein R 1 is selected from oxazole optionally substituted with 1 to 2 R 5 ; phenyl optionally substituted with 1 to 2 R 5 ; pyrazole optionally substituted with 1 to 2 R 5 ; pyridine optionally substituted with 1 to 2 R 5 ; pyridone optionally substituted with 1 to 2 R 5 ; pyrimidine optionally substituted with 1 to 2 R 5 ; and pyrazolo[1,5-a]pyrimidine optionally substituted with 1 to 2 R 5 ; and the definitions for the other variables are as defined in the first embodiment.
• R 1 is selected from oxazole optionally substituted with 1 to 2 R 5 ; phenyl optionally substituted with 1 to 2 R 5 ; pyrazole optionally substituted with 1 to 2 R 5 ; pyridine optionally substituted with 1 to 2 R 5 ; pyrimidine optionally substituted with 1 to 2 R 5 ; and pyrazolo[1,5-a]pyrimidine optionally substituted with 1 to 2 R 5 ; and the definitions for the other variables are as defined in the first embodiment.
• IRAK is an IRAK4 binding moiety represented by Formula (I), (IA) or (IB), wherein R 1 is represented by one of the following formulae:
• R 1 is represented by formula (C1), (C2), (C3), (C5), (C7) or (C8) and the definitions for the other variables are as defined in the first embodiment.
• IRAK is an IRAK4 binding moiety represented by Formula (I), (IA) or (IB), wherein R 1 is represented by one of the following formulae:
• R 1 is represented by formula (C1a), (C1c), (C1e), (C2), (C3a), (C3b), (C5a), (C7a) or (C8a) and the definitions for the other variables are as defined in the first embodiment.
• IRAK is an IRAK4 binding moiety represented by Formula (I), (IA) or (IB), wherein R 1 is represented by the following formula:
• R 1 is represented by formula (C3b) and the definitions for the other variables are as defined in the first embodiment.
• IRAK is an IRAK4 binding moiety represented by Formula (I), (IA) or (IB), wherein R 2 is hydrogen; and the definitions for the other variables are as defined in the first, second, third, fourth, fifth, sixth or seventh embodiment.
• IRAK is an IRAK4 binding moiety represented by one of the following formulae:
• the IRAK4 binding moiety is represented by formula (IA-1) or (IB-2) and the definitions for the other variables are as defined in the first embodiment.
• IRAK is an IRAK4 binding moiety represented by one of Formula (I), (IA), (IB), (IA-1) or (IB-2), wherein R 3 is C 1-4 alkyl or —OR 6 , wherein the C 1-4 alkyl is optionally substituted with at least one halogen; and R 6 is C 1-5 alkyl, C 3-6 cycloalkyl or a 4 to 7 membered fully saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the C 1-5 alkyl represented by R 6 is optionally substituted with one to three halogens, and the C 3-6 cycloalkyl represented by R 6 is optionally substituted with 1 to 3 substituents R 6b independently selected from halogen, C 1-4 alky, C 1-4 haloalkyl, and C 1-4 alkoxy.
• R 3 is C 1-4 alkyl or —OR 6 , wherein the C 1-4 alkyl is optionally substituted with at least one halogen; and R 6 is C 1-5 alkyl; and the definitions for the other variables are as defined in the first, third, fourth, fifth, sixth, seventh or eighth embodiment.
• IRAK is an IRAK4 binding moiety represented by one of Formula (I), (IA), (IB), (IA-1) or (IB-2), wherein R 3 is —CF 3 or —O—CH(CH 3 ) 2 ; and the definitions for the other variables are as defined in the first, third, fourth, fifth, sixth, seventh or eighth embodiment.
• IRAK is an IRAK4 binding moiety represented by one of Formula (I), (IA), (IB), (IA-1) or (IB-2), wherein R 3 is —O—CH(CH 3 ) 2 ; and the definitions for the other variables are as defined in the first, third, fourth, fifth, sixth, seventh or eighth embodiment.
• IRAK is an IRAK4 binding moiety represented by one of Formula (I), (IA), (IB), (IA-1) or (IB-2), wherein R 5 for each occurrence, is independently selected from C 1-4 alkyl, halogen, C 1-4 haloalkyl and C 3-4 cycloalkyl, and wherein said C 3-4 cycloalkyl is optionally substituted with 1 halo; and the definitions for the other variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, tenth, eleventh or twelfth embodiment.
• R 5 for each occurrence is independently selected from C 1-4 alkyl, halogen and C 1-4 haloalkyl; and the definitions for the other variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, tenth, eleventh or twelfth embodiment.
• IRAK is an IRAK4 binding moiety represented by one of Formula (I), (IA), (IB), (IA-1) or (IB-2), wherein R 5 for each occurrence, is independently selected from —CH 3 , —CHF 2 , —CF 3 , F, cyclopropyl, and
• R 5 for each occurrence is independently selected from —CH 3 , —CHF 2 , —CF 3 and F; and the definitions for the other variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, tenth, eleventh or twelfth embodiment.
• IRAK is an IRAK4 binding moiety represented by one of the following formulae:
• R 5 is C 1-3 alkyl, C 1-3 haloalkyl, C 3-4 cycloalkyl, and wherein said C 3-4 cycloalkyl is optionally substituted with 1 halo; and the definitions for the other variables are as defined in the first embodiment.
• the IRAK4 binding moiety represented formula (IA-1a) or (IIB-2a) R 5 is C 1-3 alkyl or C 1-3 haloalkyl; and the definitions for the other variables are as defined in the first embodiment.
• IRAK is an IRAK4 binding moiety represented by one of Formula (IA-1a) or (JIB-2a), wherein R 5 is CH 3 , CHF 2 , CF 3 , cyclopropyl, or
• R 5 is CH 3 , CHF 2 , or CF 3 , and the definitions for the other variables are as defined in the fifteenth embodiment.
• DSM Degradation Signaling Moiety
• the degradation signaling moiety (DSM) in compounds of formula (A) or a pharmaceutically acceptable salt thereof can be a suitable moiety that binds to an E3 ubiquitin ligase (e.g., the cereblon protein), for example, a degron or E3 ubiquitin ligase binding or targeting moiety described in WO2020/210630 titled “Tricyclic Degraders of Ikaros and Aiolos”; WO2020/181232 titled “Heterocyclic Compounds for Medical Treatment”; WO2020/132561 titled “Targeted Protein Degradation”; WO2019/204354 titled “Spirocyclic Compounds”; WO2019/099868 titled “Degraders and Degrons for Targeted Protein Degradation”; WO2018/237026 titled “N/O-Linked Degrons and Degronimers for Protein Degradation”; WO2017/197051 titled “Amine-Linked C3-Glutarimide Degronimers for Target
• degradation signaling moiety or E3 ubiquitin ligase binding or targeting moiety that can be used are those described in WO2015/160845; WO2016/105518; WO2016/118666; WO2016/149668; WO2016/197032; WO2016/197114; WO2017/007612; WO2017/011371; WO2017/011590; WO2017/030814; WO2017/046036; WO2017/176708; WO2017/176957; WO2017/180417; WO2018/053354; WO2018/071606; WO2018/102067; WO2018/102725; WO2018/118598; WO2018/119357; WO2018/119441; WO2018/119448; WO2018/140809; WO2018/144649; WO2018/119448; WO2018/226542; WO2019/023553, WO2019/195201, WO2019/199816, and WO2019/099926.
• DSM is a degradation signaling moiety of formula (D):
• G 1 is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl and partially saturated 4- to 11-membered heterocycle; wherein the 6- to 10-membered aryl, 5- to 10-membered heteroaryl and partially saturated 4- to 11-membered heterocycle represented by G 1 are each optionally substituted with one or more R D3 ;
• DSM is a degradation signaling moiety of formula (D), wherein Het 1 is a 4 to 7 membered monocyclic saturated heterocycle containing 1 or 2 nitrogen atoms or a 7 to 11 membered saturated spiro bicyclic heterocycle containing 1 or 2 heteroatoms selected from N and O, each of which is optionally substituted with 1 or 2 R D5 ; and the definitions for the other variables are as defined in the seventeenth embodiment.
• DSM is a degradation signaling moiety of formula (D), wherein Het 1 is piperidine, piperazine, 2-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 5-azaspiro[3.4]octane or 9-oxa-9-azaspiro[5.5]undecane, each of which is optionally substituted with 1 or 2 R D5 ; and the definitions for the other variables are as defined in the seventeenth embodiment.
• DSM is a degradation signaling moiety of formula (D-I) or (D-II):
• G 1 is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl and partially saturated 4- to 11-membered heterocycle; wherein the 6- to 10-membered aryl, 5- to 10-membered heteroaryl and partially saturated 4- to 11-membered heterocycle represented by G 1 are each optionally substituted with one or more R D3 ;
• R D2 is H or C 1-3 alkyl;
• R D3 is, for each occurrence, independently selected from H, halogen and C 1-4 alkyl;
• R D4 is C 1-3 alkyl;
• R D5 is halogen; and n is 0, 1 or 2; and the definitions for the other variables are as defined in the seventeenth embodiment.
• DSM is a degradation signaling moiety of formula (D), (D-I) or (D-II), wherein G 1 is 6- to 10-membered aryl, 5- to 10-membered heteroaryl or partially saturated 4- to 11-membered heterocycle; wherein the 6- to 10-membered aryl, 5- to 10-membered heteroaryl and partially saturated 4- to 11-membered heterocycle represented by G 1 are each optionally substituted with 1 or 2 R D3 ; and the definitions for the other variables are as defined in the seventeenth, eighteenth, nineteenth or twentieth embodiment.
• DSM is a degradation signaling moiety of formula (D), (D-I) or (D-II), wherein G 1 is selected from phenyl, pyrazolyl, pyridinyl and pyrimidinyl, 1,3-dihydro-2H-benzo[d]imidazol-2-one, indazolyl, and indolyl, each of which is optionally substituted with 1 or 2 R D3 ; and the definitions for the other variables are as defined in the seventeenth, eighteenth, nineteenth or twentieth embodiment.
• DSM is a degradation signaling moiety of formula (D), (D-I) or (D-II), wherein G 1 is represented by any one of the following formulae:
• o is 0, 1 or 2
• —* represents a bond to Z 1
• the definitions for the other variables are as defined in the seventeenth, eighteenth, nineteenth or twentieth embodiment.
• DSM is a degradation signaling moiety of formula (D), (D-I) or (D-II), wherein G 1 is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the 6- to 10-membered aryl and 5- to 10-membered heteroaryl represented by G 1 are each optionally substituted with 1 or 2 R D3 ; and the definitions for the other variables are as defined in the seventeenth, eighteenth, nineteenth or twentieth embodiment.
• DSM is a degradation signaling moiety of formula (D), (D-I) or (D-II), wherein G 1 is selected from phenyl, pyrazolyl, pyridinyl and pyrimidinyl, indazolyl, and indolyl, each of which is optionally substituted with 1 or 2 R D3 ; and the definitions for the other variables are as defined in the seventeenth, eighteenth, nineteenth or twentieth embodiment.
• DSM is a degradation signaling moiety of formula (D), (D-I) or (D-II), wherein G 1 is represented by any one of the following formulae:
• o is 0, 1 or 2
• —* represents a bond to Z 1
• the definitions for the other variables are as defined in the seventeenth, eighteenth, nineteenth or twentieth embodiment.
• DSM is a degradation signaling moiety of formula (D), (D-I) or (D-II), wherein R D1 is H, —CH 3 or F; and the definitions for the other variables are as defined in the seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth or twenty-sixth embodiment.
• DSM is a degradation signaling moiety of formula (D), (D-I) or (D-II), wherein R D2 is H; and the definitions for the other variables are as defined in the seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth or twenty-seventh embodiment.
• DSM is a degradation signaling moiety of formula (D), (D-I) or (D-II), wherein R D3 is, for each occurrence, independently selected from H, Cl, F and —CH 3 ; and the definitions for the other variables are as defined in the seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh or twenty-eighth embodiment.
• DSM is a degradation signaling moiety of formula (D), (D-I) or (D-II), wherein R D4 is —CH 3 ; and the definitions for the other variables are as defined in the seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth or twenty-ninth embodiment.
• DSM is a degradation signaling moiety of formula (D), (D-I) or (D-II), wherein R D5 for each occurrence, is independently F or OH; and the definitions for the other variables are as defined in the seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth or thirtieth embodiment.
• DSM represents any one of the following attached to L:
• L is a bond, C 1-8 alkyl or is represented by formula (L-1), (L-2) or (L-3):
• L is a bond; and the definitions for the other variables are as defined in the thirty-third embodiment.
• L is C 1-8 alkyl; and the definitions for the other variables are as defined in the thirty-third embodiment.
• L is represented by formula (L-1), (L-2) or (L-3), wherein Het 2 is selected from azetidinyl, piperidinyl and pyrrolidinyl; wherein the azetidinyl, piperidinyl and pyrrolidinyl represented by Het 2 are each optionally substituted by one or more R L1 ; and G 3 is azetidinyl, cyclohexyl or piperidinyl; wherein the cyclohexyl and piperidinyl represented by G 3 are each optionally substituted with one or more R L3 ; and the definitions for the other variables are as defined in the thirty-third embodiment.
• L is represented by formula (L-1), (L-2) or (L-3), wherein Z 2 is bond or —CH 2 —; Z 3 is —CH 2 —, —CH 2 —CH 2 —, * * —CH 2 —C(O)—* or * * —CH 2 —CH 2 —C(O)—*; and Z 4 is —CH(CH 2 Ph)- or —CH 2 —CH 2 —CH 2 —; and the definitions for the other variables are as defined in the thirty-third or thirty-sixth embodiment.
• L is represented by formula (L-1), (L-2) or (L-3), wherein R L1 is H; R L2 is H; R L3 is H; and R L4 is benzyl; and the definitions for the other variables are as defined in the thirty-third, thirty-sixth or thirty-seventh embodiment.
• L is represented by formula (L-1) and Het 2 is represented by one of the formulae:
• L is represented by formula (L-2) and G 3 is represented by one of the formulae:
• L is represented by formula (L-1) and Het 2 is:
• L is represented by formula (L-3); Z 4 is C 1-4 alkyl optionally substituted by benzyl; and R L2 is H; and the definitions for the other variables are as defined in the thirty-third embodiment.
• L is represented by any one of the following formulae:
• the compound of formula (A), or a pharmaceutically acceptable salt thereof is a compound of any one of Examples 1-87 or a pharmaceutically acceptable salt thereof.
• compositions comprising at least one compound described herein (e.g., a compound or a pharmaceutically acceptable salt thereof described in any of the embodiments described above), and at least one pharmaceutically acceptable carrier.
• the compounds of the present disclosure are typically used as a pharmaceutical composition (e.g., a compound of the present disclosure and at least one pharmaceutically acceptable carrier).
• pharmaceutically acceptable carrier includes generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, salts, preservatives, drug stabilizers, buffering agents (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, and the like), and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed.
• solvates and hydrates are considered pharmaceutical compositions comprising a compound of the present disclosure and a solvent (i.e., solvate) or water (i.e., hydrate).
• the compounds described herein can be used to cause the degradation of IRAK4 proteins.
• the compounds described herein e.g., a compound or a pharmaceutically acceptable salt thereof described in any of the embodiments described above
• the compounds or pharmaceutically acceptable salts thereof described herein can be used to modulate (e.g., decrease) the activity of IRAK4, or to otherwise affect the properties and/or behavior of IRAK4, e.g., stability, phosphorylation, kinase activity, interactions with other proteins, etc.
• the present disclosure provides methods of decreasing protein levels of IRAK4 and/or IRAK4 enzymatic activity.
• such methods include contacting a cell with an effective amount of a compound described herein (e.g., a compound or a pharmaceutically acceptable salt thereof described in any of the embodiments described above).
• One aspect of the present disclosure includes a method of treating a disorder responsive to degradation of IRAK4 and/or inhibition of IRAK4 activity in a subject comprising administering to the subject an effective amount of at least one compound described herein (e.g., a compound or a pharmaceutically acceptable salt thereof described in any of the embodiments described above), or a pharmaceutical composition described herein.
• a compound described herein e.g., a compound or a pharmaceutically acceptable salt thereof described in any of the embodiments described above
• One embodiment of the disclosure includes a method for treating an autoimmune disease, cancer, cardiovascular disease, a disease of the central nervous system, a disease of the skin, an ophthalmic disease and condition, and bone disease in a subject, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, thereby treating the autoimmune disease, cancer, cardiovascular disease, disease of the central nervous system, disease of the skin, ophthalmic disease and condition, and bone disease in the subject.
• the cardiovascular disease is selected from stroke and atherosclerosis.
• the disease of the central nervous system is a neurodegenerative disease.
• the disease of the skin is selected from rash, contact dermatitis, psoriasis, Hidradenitis Suppurativa and atopic dermatitis.
• the bone disease is selected from osteoporosis and osteoarthritis.
• the present disclosure provides methods of treating autoimmune disorders, inflammatory disorders, and cancers in a subject in need thereof comprising administering to the subject an effective amount of at least one compound described herein (e.g., a compound or a pharmaceutically acceptable salt thereof described in any of the embodiments described above), or a pharmaceutical composition described herein.
• at least one compound described herein e.g., a compound or a pharmaceutically acceptable salt thereof described in any of the embodiments described above
• autoimmune disorders includes diseases or disorders involving inappropriate immune response against native antigens, such as acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), Coeliac disease, dermatomyositis, diabetes mellitus type 1, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, cutaneous lupus erythematosus (CLE), neuromyelitis optica (NMO), mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anaemia, polymyositis, primary biliary cirrhosis, Sjogren's syndrome, temp
• the autoimmune disease is selected from rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, systemic sclerosis, and Sjogren's syndrome. In one embodiment, the autoimmune disease is type 1 diabetes.
• inflammatory disorders includes diseases or disorders involving acute or chronic inflammation such as allergies, asthma, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, e.g., Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis.
• PID pelvic inflammatory disease
• IBD inflammatory bowel disease
• reperfusion injury rheumatoid arthritis
• transplant rejection e.g., vasculitis
• vasculitis e.g., vasculitis.
• the present disclosure provides a method of treating rheumatoid arthritis or lupus.
• the present disclosure provides a method of treating multiple sclerosis.
• the present disclosure provides a method of treating systemic lupus erythematosus or atopic dermatitis.
• One embodiment of the disclosure includes a method for treating an inflammatory disease in a subject, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating the inflammatory disease in the subject.
• the inflammatory disease is a pulmonary disease or a disease of the airway.
• the pulmonary disease and disease of the airway is selected from Adult Respiratory Disease Syndrome (ARDS), Chronic Obstructive Pulmonary Disease (COPD), pulmonary fibrosis, interstitial lung disease, asthma, chronic cough, and allergic rhinitis.
• ARDS Adult Respiratory Disease Syndrome
• COPD Chronic Obstructive Pulmonary Disease
• pulmonary fibrosis pulmonary fibrosis
• interstitial lung disease asthma, chronic cough, and allergic rhinitis.
• the inflammatory disease is selected from transplant rejection, CD14 mediated sepsis, non-CD14 mediated sepsis, inflammatory bowel disease, Behcet's syndrome, ankylosing spondylitis, sarcoidosis, and gout.
• the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis.
• One embodiment of the disclosure includes a method for treating an ischemic fibrotic disease, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating the ischemic fibrotic disease in the subject.
• the ischemic fibrotic disease is selected from stroke, acute lung injury, acute kidney injury, ischemic cardiac injury, acute liver injury, and ischemic skeletal muscle injury.
• One embodiment of the disclosure includes a method for treating post-organ transplantation fibrosis, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating post-organ transplantation fibrosis in the subject.
• One embodiment of the disclosure includes a method for treating hypertensive or diabetic end organ disease, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating hypertensive or diabetic end organ disease in the subject.
• One embodiment of the disclosure includes a method for treating hypertensive kidney disease, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating hypertensive kidney disease in the subject.
• One embodiment of the disclosure includes a method for treating idiopathic pulmonary fibrosis (IPF), the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating IPF in the subject.
• IPPF idiopathic pulmonary fibrosis
• One embodiment of the disclosure includes a method for treating scleroderma or systemic sclerosis, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating scleroderma or systemic sclerosis in the subject.
• One embodiment of the disclosure includes a method for treating liver cirrhosis, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating liver cirrhosis in the subject.
• One embodiment of the disclosure includes a method for treating fibrotic diseases wherein tissue injury and/or inflammation are present, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating fibrotic diseases where tissue injury and/or inflammation are present in the subject.
• the fibrotic diseases include, for example, pancreatitis, peritonitis, burns, glomerulonephritis, complications of drug toxicity, and scarring following infections.
• Scarring of the internal organs is a major global health problem, which is the consequence of subclinical injury to the organ over a period of time or as the sequela of acute severe injury or inflammation. All organs may be affected by scarring and currently there are few therapies the specifically target the evolution of scarring. Increasing evidence indicates that scarring per se provokes further decline in organ function, inflammation and tissue ischemia. This may be directly due the deposition of the fibrotic matrix which impairs function such as in contractility and relaxation of the heart and vasculature or impaired inflation and deflation of lungs, or by increasing the space between microvasculature and vital cells of the organ that are deprived of nutrients and distorting normal tissue architecture.
• myofibroblasts themselves are inflammatory cells, generating cytokines, chemokines and radicals that promote injury; and myofibroblasts appear as a result of a transition from cells that normally nurse and maintain the microvasculature, known as pericytes.
• the consequence of this transition of phenotype is an unstable microvasculature that leads to aberrant angiogenesis, or rarefaction.
• the present disclosure relates to methods and compositions for treating, preventing, and/or reducing scarring in organs. More particularly, the present disclosure relates to methods and composition for treating, preventing, and/or reducing scarring in kidneys.
• organs include: kidney, hearts, lungs, stomach, liver, pancreas, hypothalamus, stomach, uterus, bladder, diaphragm, pancreas, intestines, colon, and so forth.
• methods and compositions described herein can be used as an antifibrotic, or used to treat, prevent, and/or reduce the severity and damage from fibrosis. It is additionally contemplated that the present disclosure, methods and compositions described herein can be used to treat, prevent, and/or reduce the severity and damage from fibrosis.
• the compounds of the present disclosure may be useful in the treatment of cancer, for example a cancer selected from solid tumor cancers and hematopoietic cancers.
• cancer includes diseases or disorders involving abnormal cell growth and/or proliferation, such as glioma, thyroid carcinoma, breast carcinoma, lung cancer (e.g. small-cell lung carcinoma, non-small-cell lung carcinoma), gastric carcinoma, gastrointestinal stromal tumors, pancreatic carcinoma, bile duct carcinoma, ovarian carcinoma, endometrial carcinoma, prostate carcinoma, renal cell carcinoma, lymphoma (e.g., anaplastic large-cell lymphoma), leukemia (e.g. acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g. microsatellite instability-high colorectal cancer).
• the present disclosure provides a method of treating leukemia or lymphoma.
• solid tumor cancers include central nervous system cancer, brain cancer, breast cancer, head and neck cancer, lung cancer; esophageal and esophagogastric junction cancer, gastric cancer, colorectal cancer, rectal cancer, anal cancer, hepatobiliary cancer, pancreatic cancer, non-melanoma skin cancer, melanoma, renal cancer, prostate cancer, bladder cancer, uterine cancer, cervical cancer, ovarian cancer, bone cancer, neuroendocrine cancer, mesothelioma cancer, testicular cancer, thymoma and thymic carcinoma, and thyroid cancer.
• hematopoietic cancers include B-cell neoplasms (including rare B-cell malignancies), Hodgkin lymphoma, non-Hodgkin lymphoma, post-transplant lymphoproliferative disorder, hairy cell leukemia, histiocytic and dendritic neoplasms.
• B-cell neoplasms include chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), Waldenstrom's macroglobulinemia, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, Marginal Zone Lymphoma, immunoblastic large cell lymphoma, Richter Syndrome, and precursor B-lymphoblastic lymphoma, primary and secondary multiple myeloma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoi
• the cancer is selected from chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), and Waldenstrom's macroglobulinemia.
• CLL chronic lymphocytic leukemia
• DLBCL diffuse large B-cell lymphoma
• DLBCL diffuse large B-cell lymphoma
• the present disclosure relates to the aforementioned methods, wherein said subject is a mammal. In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said subject is a primate. In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said subject is a human.
• an “effective dose” or an “effective amount” of the compound or pharmaceutical composition is that amount effective for treating or lessening the severity of one or more of the diseases, disorders or conditions as recited above.
• the effective dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, administered to a subject can be 10 ⁇ g-500 mg.
• the formulations may be prepared using conventional dissolution and mixing procedures.
• the bulk drug substance i.e., compound of the present disclosure or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)
• a suitable solvent in the presence of one or more of the excipients described above.
• the compound of the present disclosure is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.
• the pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug.
• an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
• Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
• the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
• the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
• composition comprising a compound of the present disclosure is generally formulated for use as a parenteral or oral administration or alternatively suppositories.
• the pharmaceutical oral compositions of the present disclosure can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions).
• the pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.
• the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Tablets may be either film coated or enteric coated according to methods known in the art.
• diluents
• compositions for oral administration include a compound of the disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
• Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
• Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
• excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
• the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
• Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
• the parenteral compositions are aqueous isotonic solutions or suspensions.
• the parenteral compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
• the compositions are generally prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
• the compounds and compositions, according to the methods of the present disclosure may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the diseases, disorders or conditions recited above.
• Administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal comprises any suitable delivery method.
• Administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal includes administering a compound described herein, or a pharmaceutically acceptable salt thereof, topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally or intravitreally to the mammal.
• Administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal also includes administering topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally or intravitreally to a mammal a compound that metabolizes within or on a surface of the body of the mammal to a compound described herein, or a pharmaceutically acceptable salt thereof.
• the compound of the present disclosure or pharmaceutical composition thereof for use in a subject is typically administered orally or parenterally at a therapeutic dose of less than or equal to about 100 mg/kg, 75 mg/kg, 50 mg/kg, 25 mg/kg, 10 mg/kg, 7.5 mg/kg, 5.0 mg/kg, 3.0 mg/kg, 1.0 mg/kg, 0.5 mg/kg, 0.05 mg/kg or 0.01 mg/kg, but preferably not less than about 0.0001 mg/kg.
• the dosage may depend upon the infusion rate at which an IV formulation is administered.
• the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated.
• a physician, pharmacist, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
• a compound or pharmaceutically acceptable salt thereof as described herein may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
• a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
• the compound or pharmaceutically acceptable salt thereof as described herein may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, or wafers, and the like.
• Such compositions and preparations should contain at least about 0.1% of active compound.
• the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
• the tablets, troches, pills, capsules, and the like can include the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; or a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent.
• binders such as gum tragacanth, acacia, corn starch or gelatin
• excipients such as dicalcium phosphate
• a disintegrating agent such as corn starch, potato starch, alginic acid and the like
• a lubricant such as magnesium stearate
• a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent.
• the present disclosure relates to the aforementioned methods, wherein said compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, rectally, intrathecally, topically or intranasally.
• the active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
• the present disclosure relates to the aforementioned methods, wherein said compound is administered parenterally.
• the present disclosure relates to the aforementioned methods, wherein said compound is administered systemically.
• Exemplary pharmaceutical dosage forms for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions.
• the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
• Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
• the preferred methods of preparation can be vacuum drying and the freeze drying techniques, which can yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
• Exemplary solid carriers can include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
• Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the compounds or pharmaceutically acceptable salts thereof as described herein can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
• Useful dosages of a compound or pharmaceutically acceptable salt thereof as described herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949, which is incorporated by reference in its entirety.
• a dose can be in the range of from about 0.1 to about 10 mg/kg of body weight per day.
• the compound or pharmaceutically acceptable salt thereof as described herein can be conveniently administered in unit dosage form; for example, containing 0.01 to 10 mg, or 0.05 to 1 mg, of active ingredient per unit dosage form. In some embodiments, a dose of 5 mg/kg or less can be suitable.
• the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals.
• the disclosed method can include a kit comprising a compound or pharmaceutically acceptable salt thereof as described herein and instructional material which can describe administering a compound or pharmaceutically acceptable salt thereof as described herein or a composition comprising a compound or pharmaceutically acceptable salt thereof as described herein to a cell or a subject.
• instructional material which can describe administering a compound or pharmaceutically acceptable salt thereof as described herein or a composition comprising a compound or pharmaceutically acceptable salt thereof as described herein to a cell or a subject.
• the subject can be a human.
• silica gel chromatography was performed using 20-40 ⁇ M (particle size), 100-200 mesh, 250-400 mesh, or 400-632 mesh silica gel using either a Teledyne ISCO Combiflash® RF, a Biotage® Isolera One 3.3.0, a Biotage® Flash Isolera Prime, a Grace Reveleris X2 with ELSD purification, a Gilson-281 with ELSD purification systems or using pressurized nitrogen ( ⁇ 10-15 psi) to drive solvent through the column (“flash chromatography”).
• DSMs Degradation Signaling Moieties
• the reaction mixture was degassed with argon for 20 minutes, after which cyclopentyl(diphenyl)phosphane; dichloromethane; dichloropalladium; iron (2.40 g, 2.94 mmol) was added and the reaction was heated at 100° C. for 6 hours while monitoring with TLC and LC-MS. After completion of the reaction, the volatiles were removed under reduced pressure and the residue was extracted with ethyl acetate (200 mL ⁇ 3) and water (200 mL). The combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
• the reaction mixture was degassed with argon for 20 minutes, after which cyclopentyl(diphenyl) phosphane; dichloropalladium; iron (1.89 g, 2.58 mmol) was added and the reaction was heated at 110° C. for 16 hours while monitoring with TLC and LC-MS.
• the catalyst was filtered off through celite bed and washed with ethyl acetate (100 mL ⁇ 3). The filtrate was washed with water (100 mL) and brine solution (100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
• reaction mixture was concentrated to a residue which was triturated with MTBE (200 mL), filtered, and the filter cake was dried under vacuum to afford 1-(5-fluoro-1-methyl-6-piperazin-1-yl-indazol-3-yl)hexahydropyrimidine-2,4-dione (2 g, 4.70 mmol, 87.47% yield) as a grey solid.
• the reaction was purged with nitrogen for 20 minutes, then charged with palladium (0) tetrakis(triphenylphosphine) (2.24 g, 1.94 mmol) and heated to 90-100° C. for 5 hours. TLC confirmed the formation of product.
• the reaction was cooled to room temperature and filtered through a celite bed and washed with EtOAc. The filtrate was taken and distilled completely under vacuum at 45° C.
• the crude product was dissolved in EtOAc (15 V) and separated with water (10 V). The organic layer was washed with water (5 V), brine (5 V), then dried over anhydrous Na 2 SO 4 . The organic layer was concentrated in vacuo at 45° C.
• 2,6-dibenzyloxypyridin-3-amine 50 g, 163.21 mmol was dissolved with THF (500 mL) and cooled to ⁇ 78° C.
• Lithium bis(trimethylsilyl)amide 40.96 g, 244.81 mmol was added dropwise, then stirred for 1 hour at ⁇ 78° C.
• 1-fluoro-3-iodo-2-nitro-benzene 43.58 g, 163.21 mmol was added dropwise as a solution in THF (500 mL) at ⁇ 78° C., then stirred for 1 hour at ⁇ 78° C.
• reaction mixture was heated at 100° C. for 12 hr.
• the reaction mixture was diluted with ethyl acetate (60 mL) and was washed with water/brine and separated. After evaporation of the organic layer the residue was purified by column chromatography to afford tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate (460 mg, 1.19 mmol, 33.56% yield).
• reaction mixture was degassed with nitrogen for 15 minutes before cyclopentyl(diphenyl)phosphane; dichloromethane; dichloropalladium; iron (4.79 g, 5.86 mmol) was added. After addition, the reaction mixture was stirred at 100° C. for 12 hours in a sealed tube. Upon completion of the reaction, the reaction mixture was filtered through a celite bed which was washed with ethyl acetate several times. The combined organic layers were washed with water/brine and separated.
• the reaction mixture was poured into aqueous sodium bicarbonate solution (200 mL) and the aqueous phase was extracted with ethyl acetate (80 mL ⁇ 3). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The resulting residue was then dissolved in THF (500 mL), sodium bicarbonate (27.72 g, 329.96 mmol) and N-bromosuccinimide (58.73 g, 329.96 mmol) were added at 0° C. and the solution was stirred at 25° C. for 2 hours.
• THF 500 mL
• sodium bicarbonate 27.72 g, 329.96 mmol
• N-bromosuccinimide 58.73 g, 329.96 mmol
• Example 2 Compound of Example 2 was prepared substantially following the synthesis of Example 1
• Example 14 was prepared substantially following the synthesis of Example 11 using 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione Isomer 2.
• Example 15 was prepared substantially following the synthesis of Example 11, using 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione Isomer 1.
• Example 31 was prepared substantially following the synthesis of Example 30.
• Example 32 was prepared substantially following the synthesis of Example 30.
• Example 34 was prepared substantially following the synthesis of Example 30, except starting with N-[2-(azetidin-3-yl)-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide.
• reaction mixture was quenched with saturated cold ammonium chloride, extracted with ethyl acetate two times, the ethyl acetate layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to a afford 1-[4-(benzyloxymethyl)cyclohexyl]-2-chloro-ethanone (11 g, 39.18 mmol, 89.36% yield) as yellow liquid.
• Example 36 was prepared substantially following the synthesis of Example 35.
• Example 37 was prepared substantially following the synthesis of Example 35.
• Example 39 was prepared substantially following the synthesis of Example 35.
• Example 40 was prepared substantially following the synthesis of Example 35.
• Example 41 was prepared substantially following the synthesis of Example 35.
• Example 45 was prepared substantially following the synthesis of Example 35.
• Example 46 was prepared substantially following the synthesis of Example 35.
• Example 48 was prepared substantially following the synthesis of Example 47.

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